Alcohol withdrawal syndrome and sympathetic nervous system function – Biological Research at National Institute of Alcohol Abuse and Alcoholism
Alcohol Withdrawal Syndrome and Sympathetic Nervous System Function
Alcohol withdrawal syndrome is a common and potentially serious complication of alcoholism that generally occurs from 6 to 48 hours after the last drink. Among its early symptoms are anxiety, agitation, tremor, profuse sweating, elevated blood pressure, increased heart rate, anorexia, and reduced sleep. In severe cases the syndrome may progress to include seizures.
The similarity between these symptoms and those of overactivity of the sympathetic nervous system has long been recognized. The sympathetic nervous system helps the body to cope with challenges from the outside environment and generally is activated in situations involving stress or strong emotions. In the Laboratory of Clinical Studies of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), we have been investigating the physiology of alcohol withdrawal and its relationship to sympathetic nervous system function. Results of this research have led to the development of drugs that may eventually be used to treat ethanol-induced intoxication in humans.
NOREPINEPHRINE PRODUCTION AND WITHDRAWAL
The sympathetic nervous system is partly under the control of the hypothalamus, a tiny region of the brain located immediately above the pituitary gland. The main chemical messenger associated with sympathetic nervous system functioning is the neurotransmitter norepinephrine. To confirm that sympathetic hyperactivity is involved in alcohol withdrawal, we measured a metabolite of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), in cerebrospinal fluid (Hawley et al. 1985). This measurement provides an indirect indication of norepinephrine activity.
We found that norepinephrine production in the central nervous systems of alcoholics increased significantly during withdrawal compared with that of controls who were age- and sex-matched. Norepinephrine production then decreased significantly during the 10-day period following acute withdrawal. The rate at which withdrawal symptoms subsided during the period following acute withdrawal correlated strongly with the rate of decrease of MHPG. These results suggest that the degree of enhanced norepinephrine production is associated with the severity of withdrawal symptoms.
Why might the norepinephrine-producing (noradrenergic) nerve cells in the central nervous system become overactive? The activity of these neurons is regulated by various hormones and neurotransmitters, some of which are excitatory and some inhibitory (Figure 1). Each of these regulatory substances functions by binding to specific receptor sites located on the surface of the neuron. Since these substances cause an action to occur, they are called agonists. The combined action of these excitatory and inhibitory agonists (called antagonists) determines how often the noradrenergic neuron fires, and how much norepinephrine it releases.
One important mechanism that regulates the activity of neurons is feedback inhibition, by which a released neurotransmitter acts on the neuron to prevent further release of that same neurotransmitter. In noradrenergic nerve cells, feedback inhibition is mediated at alpha-2 receptors.
Therefore, we investigated the possibility that the increased sympathetic activity seen in withdrawal may result from faulty feedback through the alpha-2 receptor. Our first consideration was that, curiously enough, the agonist responsible for feedback inhibition of norepinephrine release may not be norepinephrine itself.
Apparently, certain cells that are clustered around nerve endings–presumably the cells known as astrocytes–contain an enzyme that converts norepinephrine to the related compound epinephrine. Noradrenergic (norepinephrine) nerve cells in the hypothalamus probably lack this enzyme, known as phenylethanolamine-N-methyltransferase (PNMT) (Mefford 1987a). Epinephrine (also known as adrenalin) is familiar as the “fight-or-flight” hormone secreted into the blood by the adrenal medulla. Its presence in the brain was overlooked for many years because of its low concentration there relative to norepinephrine.
EPINEPHRINE AND INTOXICATION
Various lines of evidence indicate that epinephrine may be the primary agonist at the alpha-2 receptor (Stolk et al. 1984; Vantini et al. 1984). Epinephrine also has been implicated in the addictive and positively reinforcing effects of alcohol. In one series of experiments on rats, electrodes were implanted in the medial forebrain bundle, a group of fibers through which information is projected into and out of the hypothalamus (Katz and Carroll 1977; 1978). By pressing a lever, the rats self-administered self-administered an electrical impulse to this part of the brain. (This type of self-stimulation seems to provide a sense of reward–positive reinforcement–and is considered by many investigators to be an analog of addictive behavior.)
When the rats were treated with various PNMT inhibitors to prevent the synthesis of epinephrine, the rate at which they pressed the lever declined. This decrease in self-stimulation was dose-dependent; that is, the higher the dosage of PNMT inhibitor, the less often the rat pressed the lever. These experiments indicate that epinephrine might be involved in this type of reward response, presumably by acting as an agonist at alpha-2 receptors.
We therefore studied the effects of ethanol on epinephrine concentrations in the rat hypothalamus, both during intoxication and in withdrawal (Mefford 1987b). Intoxication was produced by allowing rats to breathe ethanol vapors in an airtight chamber to ensure continuous and consistent blood ethanol levels. The animals were exposed in this manner for 24 hours (acute exposure) or for 14 days (chronic exposure). To produce withdrawal, chronically exposed animals were removed from exposure 8 to 12 hours before testing.
The resultant epinephrine release in the hypothalamus was interpreted to have increased during both acute and chronic ethanol exposure, and the degree of depletion of tissue epinephrine content correlated highly with blood ethanol concentrations. Norepinephrine release in the hypothalamus had also increased, although it correlated less well with blood ethanol concentrations. Hypothalamic epinephrine had been depleted by more than 80 percent during withdrawal.
We then attempted to confirm the role of excess epinephrine in the intoxicating effects of ethanol. PNMT inhibitors were administered to experimental rats to prevent epinephrine synthesis. Five minutes later, these rats and controls were exposed to 2.4 g/kg of ethanol. Rats that had been treated with epinephrine synthesis inhibitors were significantly less intoxicated than controls, as measured by behavior, mobility, and righting reflex (Mefford 1987b). Intoxication was also significantly inhibited by atipamezole, a highly specific alpha-2 antagonist (Lister et al. 1988).
Thus, the release of epinephrine appears to be an important step in the development of ethanol-induced intoxication. The reason for enhanced epinephrine turnover during intoxication, however, is unclear. One possible explanation is that the slightly increased norepinephrine release that occurs during intoxication provides a readily available supply of raw material for epinephrine synthesis. The increased uptake of norepinephrine into PNMT-containing cells may also play a role. In any case, the data suggest the possibility of treating ethanol intoxication by inhibiting PNMT or by selectively blocking alpha-2 receptors.
The most specific alpha-2 antagonist that is currently available is atipamezole. This drug does not increase anxiety in animals, nor does it lower the seizure threshold–both harmful side effects that might be expected from an alpha-2 antagonist and that are characteristics of PNMT inhibitors. This suggests the possibility of administering atipamezole to alcoholics, perhaps in an emergency room setting, where it might be important to get the patient to behave more coherently while avoiding excess sedation.
Moreover, by reducing the positively reinforcing effects of ethanol, alpha-2 antagonists might actually change the subjective experience of ethanol intoxication, which would make them useful in the treatment of alcoholism itself.
THE PHYSIOLOGY OF WITHDRAWAL
Epinephrine’s potential role in mediating certain symptoms of alcohol-induced intoxication may provide important insight into the physiology of withdrawal. As mentioned earlier, our studies show a highly significant decrease in epinephrine content during ethanol withdrawal, which may result in the reduced concentration of agonist at the alpha-2 receptors. The consequent lack of regulatory control may be responsible for hyperactivity of the sympathetic nervous system.
At the same time, the alcoholic’s alpha-2 receptors may decrease in number or in sensitivity in response to the high levels of epinephrine that are presumed to be present during intoxication. This response, known as downregulation, is a compensatory mechanism for damping down the effect of fluctuations in neurotransmitter concentration. In either case, it appears that during withdrawal the alcoholic’s noradrenergic neurons are unable to regulate their fixing and that an appropriate alpha-2 receptor agonist would reduce the firing rate of these neurons.
To investigate this possibility, Dr. David Nutt tested alcoholics with clonidine, an alpha-2 agonist commonly used to treat withdrawal. Intravenous clonidine significantly improved such alcohol withdrawal symptoms as tremor, agitation, and sweating, and also alleviated symptoms of depression. Nutt’s findings were consistent with those regarding reduced alpha-2 receptor sensitivity (Nutt 1987).
To summarize the postulated sequence of events, chronic alcohol exposure results in a downregulation of the alpha-2 receptor, while epinephrine is depleted during withdrawal. The consequent lack of inhibitory control over noradrenergic neurons leads to overactivity, both within the central nervous system and peripherally in the sympathetic nervous system.
CORTISOL AND WITHDRAWAL
Ethanol-induced overactivity of the central nervous system has a potentially dangerous consequence that has been overlooked until recently: a significant increase in plasma cortisol levels.
Cortisol is a steroid hormone secreted by the adrenal cortex in response to stressful or novel situations. Its output is controlled in part by the hypothalamus. The consequences of activating the adrenal cortex are far-reaching and include growth inhibition and changes in carbohydrate metabolism, immune and inflammatory responses, and reproductive functions.
These changes are adaptive when the organism is facing an acute emergency. However, persistently elevated levels of cortisol may decrease a person’s ability to resist infection while accelerating the development of high blood pressure, atherosclerosis, and gastric ulcers. Moreover, results of recent animal studies (Sapolsky et al. 1986) suggest that excess levels of cortisol are toxic to neurons in the hippocampus, a part of the brain thought to be particularly important for memory functions and mood control.
Disturbances in the diurnal pattern of cortisol concentration have been reported during alcohol withdrawal (Noth and Walter 1984; Valimaki et al. 1984), but these changes are not well described. Therefore, we measured cortisol output in a number of alcoholics who were undergoing withdrawal at the inpatient research unit of the NIAAA clinical center. Preliminary findings demonstrated an increase of more than 40 percent in cortisol levels throughout day 1, with a return to control levels by day 7 (Risher-Flowers et al. 1988).
Moreover, a highly significant shortening of the diurnal cortisol rhythm during the first week following withdrawal was also observed, which indicates a major derangement in the control of cortisol output. This derangement probably occurs at the level of the central nervous system. Furthermore, a highly significant negative correlation was found between the severity of withdrawal and the period of the cycle; in other words, the more severe the withdrawal, the shorter the cortisol cycle.
Cortisol levels in alcoholics who are undergoing withdrawal are similar to those levels observed in patients with postoperative trauma or mild Cushing’s syndrome, a disorder characterized by hypersecretion of cortisol. These levels may contribute directly to such withdrawal symptoms as weakness, fatigue, mental confusion, and depression (Risher-Flowers et al. 1988). We postulate that repeated bouts of elevated cortisol during successive withdrawal episodes may result in hippocampal damage and the development of an organic brain syndrome.
In light of these data, it may be inappropriate to treat ethanol withdrawal by psychosocial means alone. The disturbance of the rhythm of cortisol production represents a potentially neurotoxic condition that requires vigorous medical treatment. The best-known pharmacological agents for treating withdrawal are the benzodiazepines. These drugs act on the inhibitory GABA-A receptor complex (Figure 1), for which the endogenous agonist is the amino acid gamma-aminobutyric acid.
We currently are studying the efficacy of a subclass of these drugs, the triazolobenzodiazepines, in ethanol withdrawal, because they are not only benzodiazepine receptor agonists but relatively potent alpha-2 receptor agonists as well (William Z. Potter, personal communication, 1989). There is also some indication that one of them, alprazolam, is capable of prolonging the abnormally compressed cortisol cycle during withdrawal.
We began by observing the clinical phenomena and pathophysiology of alcohol withdrawal, which we then studied further in animals. We now are performing investigations at the molecular level, directly elucidating the role of receptor mechanisms. With our improved understanding of these phenomena, we will develop what we hope to be new, efficacious treatments for certain conditions that are associated with alcohol abuse and alcoholism. [Figure 1 Omitted]
MARKKU LINNOILA, M.D., PH.D., is chief of the Laboratory of Clinical Studies in the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.
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